Cardiac chamber remodeling following myocardial infarction or in response to hypertension, may lead to left ventricular hypertrophy and cardiac failure. Preconditioning, or ischemic adaptation, represent the intrinsic capacity of the heart to protect itself from ischemic injury. The molecular of this phenomenon remains to be further characterized. Clinical and experimental indicate that hypertrophied hearts are more vulnerable to ischemic insult compared to non-hypertrophied hearts. In non-hypertrophied myocardium, cardiac preconditioning can attenuate ischemia/reperfusion induced contractile dysfunction via G-protein coupled receptor signaling. Our preliminary data suggest that compensated hypertrophied hearts exhibit enhanced ischemic tolerance after preconditioning compared to non-hypertrophied hearts. This provocative observation suggests that the signaling pathways involved in adaptive hypertrophy may enhance ischemic tolerance. Moreover, we have observed that this relative preservation of ischemic adaptation in the hypertrophied heart is lost in a time-dependent manner as the heart transitions from compensated hypertrophy to cardiac failure. The purpose of this project is to define the molecular pathways of ischemic adaptations in hypertrophied myocardium. It is anticipated that these new mechanistic insights will advanced our understanding of ischemic/reperfusion injury and begin to identify therapeutic targets that may improve myocardial function following ischemic injury in the hypertrophied heart. Ischemic heart disease accounts for more than 600,000 deaths annually in the United States. Recent advances in the medical management of acute coronary syndromes and cardioprotective strategies used during coronary revascularization have increased patient survival after acute myocardial infarction. Despite this progress, complications may result as the necrotic myocardium heals and patients may go on to develop LVH and congestive heart failure. The mechanisms involved in the transition from compensated hypertrophy to heart failure are complex. Overall, these studies will be the first to definitively establish the role of the G- protein-coupled alpha-adrenergic pathway as a critical determinant of preconditioning in hypertrophied hearts. Defining the mechanisms of ischemic tolerance of hypertrophied myocardium may lead to enhanced cardioprotective strategies that will minimize ischemic injury in patients with hypertension and left ventricular hypertrophy.